Recognition Sites for Antidepressant Drugs

Chuang, De‐Maw; Costa, E.

doi:10.1007/978-1-4684-4568-8_11

Cited by 4 publications

(3 citation statements)

References 142 publications

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“…In the CNS, P-adrenergic receptors can be down-regulated by pharmacological manipulations. For example, chronic treatment of experimental animals with various antidepressant drugs is known to cause a loss of P-adrenergic receptors in the brain, and this receptor downregulation is generally believed to be relevant to the therapeutic action of these drugs (reviewed by Chuang and Costa, 1984). However, little is known as to whether P-receptor internalization occurs in the CNS.…”

mentioning

confidence: 99%

Detection and characterization of beta-adrenergic receptors and adenylate cyclase in coated vesicles isolated from bovine brain

Chuang¹,

Dillon‐Carter²,

Jw³

et al. 1986

J. Neurosci.

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To assess whether internalization of beta-adrenergic receptor occurs in the CNS, we have isolated clathrin-coated vesicles from bovine forebrain and examined them for the presence of beta-adrenergic receptor binding and adenylate cyclase activities. A coated vesicle enriched preparation isolated by successive D2O-Ficoll density gradient centrifugations was applied to a glass bead permeation column to achieve further purification. Two major peaks of protein were eluted from the column and monitored by electron microscopy and SDS-PAGE. Peak II contained almost exclusively coated vesicles (98%), whereas peak I, which appeared in the void volume, contained larger smooth vesicles and few coated vesicles. beta-Adrenergic receptor binding to peaks I and II was measured with 125I-cyanopindolol (CYP) as ligand in Sepharose 4B column assays. 125I-CYP was found to bind specifically and saturably to both peaks I and II with a Bmax of 28 +/- 4 and 32 +/- 3 fmol/mg protein, respectively. 3H-CGP 12177, a hydrophilic beta-adrenergic receptor ligand, did not label receptors present in peak II, but it specifically bound to synaptic plasma membranes (SPM) prepared from bovine hippocampus and, to a lesser extent, to peak I. These results suggest that receptors present in coated vesicles are cryptic in nature. In the displacement of 125I-CYP binding by (-)-isoproterenol, addition of 50 microM GppNHp caused a significant "right shift" with SPM and peak I but not the peak II preparation. Adenylate cyclase activities could also be detected in both peaks I and II (specific activities, 21 +/- 0.6 and 24 +/- 0.5 pmol cAMP/mg protein/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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confidence: 99%

Detection and characterization of beta-adrenergic receptors and adenylate cyclase in coated vesicles isolated from bovine brain

Chuang¹,

Dillon‐Carter²,

Jw³

et al. 1986

J. Neurosci.

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“…The role of the different imipramine binding sites is still a matter of debate, It has been suggested that the high-affinity site mediates the action of imipramine in inhibiting the neuronal uptake of serotonin Paul et al, 1981;Chuang and Costa, 1984) coupled in allosteric fashion with the substrate recognition site for serotonin uptake (Sette et al, 1983;Barbaccia et al, 1983;Meyerson, 1983, 1985;Segonzac et al, 1985). The apparent discrepancy between the potency of imipramine in inhibiting high-affinity binding of [3H]imipramine to brain membranes (IC50 in the low nanomolar range) and in inhibiting uptake of serotonin into synaptosomes (low micromolar range) can be explained by the difference in temperature at which these two assays are performed (Reith et al, 1984~).…”

Section: Characteristics and Possible Role Of High-and Low-affinity Smentioning

confidence: 99%

“…Numerous studies have explored the association between the high-affmity binding of [3H]imipramine and the neuronal uptake of serotonin in the brain of various species Paul et al, 1981;Chuang and Costa, 1984; for more citations, see Langer et al, 1984). In the mouse cerebral cortex, the high-affinity binding is driven by the enthalpy change (Reith et al, 1984a) and not by hydrophobic forces (Reith et al, 19846).…”

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Binding of [³H]Imipramine to Mouse Cerebrocortical Membranes and to Glass Fiber Filters

Reith

1986

Journal of Neurochemistry

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It was suggested in a recent report by Phillips et al. [J. Neurochem. 43, 479-486 (1984)] that the low-affinity binding of [3H]imipramine in the mouse cerebral cortex could in fact represent binding of [3H]imipramine to the GF/B glass fiber filters used to terminate the assays. The present study demonstrates that this is not the case and advances two lines of evidence: (a) For saturation analysis, mouse cerebrocortical membranes were incubated with [3H]imipramine concentrations between 0.8 nM and 3.6 microM, and parallel incubations were carried out with buffer replacing the brain membranes. The same low-affinity component, in addition to the high-affinity component, was present in the binding of [3H]imipramine to brain membranes plus GF/B filters (uncorrected data), and in that to brain membranes alone (corrected data). (b) Dissociation experiments, in which filter binding is equal for all samples and dissociation time is the only variable, clearly indicated the nonhomogeneity of [3H]imipramine binding. Our results, however, do show that binding to recently purchased GF/B filters is not a negligible phenomenon in saturation experiments. Relatively lower binding was found to GF/C, GF/F, Gelman A/E, and Reeves Angel 934 AH filters; pretreatment of GF/B filters with polyethyleneimine (PEI) reduced binding to a greater extent in the single manifold than in the cell harvester.

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¹³C NMR studies of the solution molecular dynamics of tricyclic antidepressants

Craik¹,

Munro²

1990

Magnetic Reson in Chemistry

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"C NMR spin-lattice relaxation times (T,s) and nuclear Overhauser enhancements (NOE's) were measured for a series of clinically used tricyclic antidepressants (TCAs), imiprarnine (l), amitriptyline (2), doxepin (3) and dothiepin (4), at two magnetic field strengths (corresponding to "C frequencies of 75 and 100 MHz). The measurements were carried out at a range of solution concentrations in CDCI, and D,O in order to determine the factors that influence overall and internal molecular dynamics in these systems. Both the hydrochloride salts and free bases were examined. For solutions in CDCI, over a range of concentrations, or for lowconcentration (0.03 M) solutions in D,O, T, and NOE measurements were independent of magnetic field strength, indicating that motion of the TCAs was in the 'extreme narrowing limit.' In contrast, for 0.3 M solutions of the hydrochloride salts in D,O, T , and NOE measurements were field dependent, indicating the presence of significantly slower molecular mobility. It is proposed that micelles are present at this concentration and are responsible for reduced overall tumbling of the TCAs. Several degrees of internal motion were detected by the relaxation and T, measurements, viz. rapid flexing motion of the benzylic bridging carbons in the central seven-membered ring and segmental motion of the sidechain. From an examination of the effect of solvent, concentration and protonation state of the side-chain on the latter motion, it was possible to derive information on side-chain conformations and interactions.

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Recognition Sites for Antidepressant Drugs

Cited by 4 publications

References 142 publications

Detection and characterization of beta-adrenergic receptors and adenylate cyclase in coated vesicles isolated from bovine brain

Detection and characterization of beta-adrenergic receptors and adenylate cyclase in coated vesicles isolated from bovine brain

Binding of [³H]Imipramine to Mouse Cerebrocortical Membranes and to Glass Fiber Filters

¹³C NMR studies of the solution molecular dynamics of tricyclic antidepressants

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Recognition Sites for Antidepressant Drugs

Cited by 4 publications

References 142 publications

Detection and characterization of beta-adrenergic receptors and adenylate cyclase in coated vesicles isolated from bovine brain

Detection and characterization of beta-adrenergic receptors and adenylate cyclase in coated vesicles isolated from bovine brain

Binding of [3H]Imipramine to Mouse Cerebrocortical Membranes and to Glass Fiber Filters

13C NMR studies of the solution molecular dynamics of tricyclic antidepressants

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Binding of [³H]Imipramine to Mouse Cerebrocortical Membranes and to Glass Fiber Filters

¹³C NMR studies of the solution molecular dynamics of tricyclic antidepressants